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sábado, 24 de maio de 2014

Many mental illnesses reduce life expectancy more than heavy smoking

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The average reduction in life expectancy in people with bipolar disorder is between nine and 20 years, while it is 10 to 20 years for schizophrenia, between nine and 24 years for drug and alcohol abuse, and around seven to 11 years for recurrent depression.

Oxford researchers say their figures on life expectancy should galvanize governments and health and social services to put a much higher priority on how mental health services can prevent early deaths.

Mental health has not seen the same public health priority as smoking, say the Oxford scientists, despite these stark figures and the similar prevalence of mental health problems.

One in four people in the UK will experience some kind of mental health problem in the course of a year, it is estimated. Around 21% of British men and 19% of women smoke cigarettes.

The Oxford University researchers report their findings in the open access journal World Psychiatry. The study was funded by the Wellcome Trust.

The researchers searched for the best systematic reviews of clinical studies which reported mortality risk for a whole range of diagnoses -- mental health problems, substance and alcohol abuse, dementia, autistic spectrum disorders, learning disability and childhood behavioral disorders. Twenty review papers were identified, including over 1.7 million individuals and over 250,000 deaths.

They repeated searches for studies and reviews reporting life expectancy and risk of dying by suicide, and compared the results to the best data for heavy smoking.

The loss of years among heavy smokers is eight to 10 years.

All diagnoses studied showed an increase in mortality risk, though the size of the risk varied greatly. Many had risks equivalent to or higher than heavy smoking.

Dr Seena Fazel of the Department of Psychiatry at Oxford University said: 'We found that many mental health diagnoses are associated with a drop in life expectancy as great as that associated with smoking 20 or more cigarettes a day.

'There are likely to be many reasons for this. High-risk behaviors are common in psychiatric patients, especially drug and alcohol abuse, and they are more likely to die by suicide. The stigma surrounding mental health may mean people aren't treated as well for physical health problems when they do see a doctor.'

One problem is the tendency to separate mental and physical illness, explains Dr Fazel. 'Many causes of mental health problems also have physical consequences, and mental illness worsens the prognosis of a range of physical illnesses, especially heart disease, diabetes and cancer. Unfortunately, people with serious mental illnesses may not access healthcare effectively,' says Dr Fazel.

Dr Fazel is certain: 'All of this can be changed. There are effective drug and psychological treatments for mental health problems. We can improve mental health and social care provision. That means making sure people have straightforward access to health care and appropriate jobs and meaningful daytime activities. It'll be challenging, but it can be done.'

He notes: 'Beyond that, psychiatrists have a particular responsibility as doctors to ensure that the physical health of their patients is not neglected. De-medicalization of psychiatric services mitigates against that.'

He adds: 'What we do need is for researchers, care providers and governments to make mental health a much higher priority for research and innovation. Smoking is recognized as a huge public health problem. There are effective ways to target smoking, and with political will and funding, rates of smoking-related deaths have started to decline. We now need a similar effort in mental health.'

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, said: 'People with mental health problems are among the most vulnerable in society. This work emphasizes how crucial it is that they have access to appropriate healthcare and advice, which is not always the case. We now have strong evidence that mental illness is just as threatening to life expectancy as other public health threats such as smoking.'

Story Source:

The above story is based on materials provided by University of Oxford. Note: Materials may be edited for content and length.

Women with diabetes 44 percent more likely to develop coronary heart disease than men with diabetes, study of 850,000 people shows

A systematic review and meta-analysis of some 850,000 people published in Diabetologia (the journal of the European Association for the Study of Diabetes) shows that women with diabetes are 44% more likely to develop coronary heart disease (CHD) than men with diabetes independent of sex differences in the levels of other major cardiovascular risk factors. The research is by Professor Rachel Huxley, School of Population Health, University of Queensland, Australia; Dr Sanne Peters, University of Cambridge, UK, and University Medical Center Utrecht, the Netherlands, and Professor Mark Woodward, George Institute for Global Health, Sydney, Australia.

The data used in the study stretches back almost 50 years, from 1966 to 2011, and includes 64 studies, 858,507 people and 28,203 incident CHD events. Women with diabetes were almost 3 times more likely to develop CHD (actual relative risk 2.82) compared with women without diabetes, while men with diabetes were only twice as likely (actual relative risk 2.16) to develop CHD than men without diabetes. Combining the two sets of data showed that women with diabetes were 44% more likely to develop CHD than men with diabetes even after consideration was made for sex differences in other CHD factors.

The authors say that this study, the largest ever of its kind backs up findings from a smaller analysis including fewer studies that showed a 46% increased risk of dying from CHD in women with diabetes compared with men with diabetes. In this new analysis by Huxley and colleagues, the sex difference in diabetes-related risk for incident CHD was consistent across subgroups defined by age and region and remained unchanged after excluding non-fatal CHD events. They note that in another previous study they authored, diabetes in women increased the risk of stroke by 25% compared with diabetes in men. They say: "Taken together, these data provide convincing evidence that diabetes poses a greater relative risk for cardiovascular diseases in women than in men."

Several possible reasons for the difference are discussed by the authors. Women have, particularly in the past, been undertreated for risk factors for cardiovascular disease (evident in studies from 1985 and before). However, even in more contemporary populations, when diabetes is treated similar to men, women have generally been less likely to achieve treatment targets. The authors (along with others before them) speculate that women may have to metabolically deteriorate further than men to become diabetic, so they are at a worse starting point even before treatment begins. Furthermore, in the prediabetic state where glucose tolerance may already be impaired but does not meet all diagnostic criteria of diabetes, risk factor levels are more elevated in women than in men. For example, in the UK General Practice Research Database, the BMI of individuals at the time of diabetes diagnosis was, on average, almost two whole units higher (1.8 kg/m2) in women than in men.

The authors say: "It is conceivable, therefore, that the diabetes-related excess risk of CHD in women may be due to a combination of both a greater deterioration in cardiovascular risk factor levels and a chronically elevated cardiovascular risk profile in the prediabetic state, driven by greater levels of adiposity in women compared with men."

They add: "If confirmed, the implementation of sex-specific interventions before diabetes becomes manifest -- such as increased screening for prediabetes, especially in women, combined with more stringent follow-up of women at high risk for diabetes, such as women with a history of gestational diabetes -- could have a substantial impact on the prevention of CHD."

Regarding the role of doctors, the authors say: "Physicians may be more likely to recognize the early symptoms of CHD in men than women because of men's higher absolute risk, and thus sex differences in medication use and risk factor control may still exist. Greater awareness of early symptoms of CHD in women and sex-specific therapeutic risk factor management, irrespective of the presence of diabetes, will be the best way to improve clinical outcomes in both women and men."

They conclude: "Women with diabetes have a 44% greater risk of incident CHD compared with men with diabetes. Further studies are warranted to determine the actual mechanisms responsible for the difference in diabetes-related coronary risk between the sexes."

Story Source:

The above story is based on materials provided by Diabetologia. Note: Materials may be edited for content and length.

Journal Reference:

Sanne A. E. Peters et al. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia, May 2014 DOI: 10.1007/s00125-014-3260-6

One-third of all brain aneurysms rupture: size is not a significant risk factor

May 22 / 2014

University of Helsinki

Approximately one third of all brain aneurysms rupture during a patient's lifetime, resulting in a brain haemorrhage. A recent study demonstrates that, unlike what was previously assumed, the size of the aneurysm does not significantly impact the risk of rupture. The total number of individual risk factors is more important. Smoking, for example, increases the risk for ruptures, particularly in women.

Brain aneurysm.

Approximately one third of all brain aneurysms rupture during a patient's lifetime, resulting in a brain haemorrhage. A recent Finnish study demonstrates that, unlike what was previously assumed, the size of the aneurysm does not significantly impact the risk of rupture. The total number of individual risk factors is more important. Smoking, for example, increases the risk for ruptures, particularly in women.

The lifetime risk for rupture of a brain aneurysm depends heavily on the patient's overall load of risk factors. However, a recent study by researchers from the University of Helsinki and Helsinki University Central Hospital demonstrated that the size of an aneurysm has no great significance on the risk of rupture. The total number of individual risk factors is more important.

This is a unique study in that it monitored aneurysm patients over their entire lifetimes, whereas typical follow-up studies last only between one and five years in duration. The study is also exceptionally broad in scope; Docent Seppo Juvela points out that the only other place where a study of similar scope has been conducted is Japan.

"It is unlikely that another similar, non-selected lifetime follow-up study on aneurysm patients will ever be conducted again," he states.

Current care practices are based largely on the results of previous, shorter studies. Such studies have shown that the size of the aneurysm is the most significant factor predicting its risk for rupture. Consequently, small (<7mm) aneurysms have often been left untreated, even though such aneurysms have also been known to rupture and cause brain haemorrhages.

The new study established that approximately one third of all aneurysms and up to one fourth of small aneurysms will rupture during a patient's lifetime. The risk of rupture is particularly high for female smokers with brain aneurysms of seven millimetres or more in diameter. What surprised the researchers most was that the size of an aneurysm had little impact on its risk for rupture, particularly for men, despite a previously presumed correlation. In addition, the risk of rupture among non-smoking men was exceptionally low.

"This is not to say that aneurysms in non-smoking men never rupture, but that the risk is much lower than we previously thought. This means treating every unruptured aneurysm may be unnecessary if one is discovered in a non-smoking man with low blood pressure," Juvela clarifies.

But why have previous studies not reached these same results if they are so obvious?

"It is difficult to conduct reliable epidemiological research in brain aneurysms. The past 10-15 years have seen a distortion in the field due to a very limited group of researchers determining the direction for research. Now the situation is clearly changing, and clinically reasonable, population-based studies using non-selected data are on the rise again," states Dr. Miikka Korja of the HUCS neurosurgery clinic.

Finland has a strong tradition of studying the prevalence, risk factors and care of brain aneurysms, and the Helsinki University Central Hospital is one of the world's leading units to provide treatment for brain aneurysms. Major studies in the field published by Finnish researchers include the world's most extensive twin study on the hereditability of subarachnoid haemorrhage, the largest follow-up study on subarachnoid haemorrhages among diabetics, the most extensive study on the life expectancy of subarachnoid haemorrhage survivors and a study on the risk factors for subarachnoid haemorrhages using the most extensive population data.

Story Source:

The above story is based on materials provided by University of Helsinki. The original article was written by Päivi Lehtinen. Note: Materials may be edited for content and length.

Journal Reference:

M. Korja, H. Lehto, S. Juvela. Lifelong Rupture Risk of Intracranial Aneurysms Depends on Risk Factors: A Prospective Finnish Cohort Study. Stroke, 2014; DOI: 10.1161/STROKEAHA.114.005318

Antibiotic crisis needs united global response, experts say

Growing resistance to antibiotics and other drugs demands a coordinated global response on the same scale as efforts to address climate change, experts say.

Without an international commitment to tackle the issue, the world faces a future in which simple infections that have been treatable for decades become deadly diseases, they warn.

Resistance to antibiotics to tackle bacterial infections and antimicrobial drugs used to treat parasites, viruses and fungi is spreading at an alarming rate. Treatment for many infectious diseases is now reliant on just one or two drugs.

Professor Mark Woolhouse, of the University of Edinburgh, and Dr Jeremy Farrar, Director of the Wellcome Trust, outlined their concerns at an event hosted by the Royal Society in London and in a Comment piece published online in the journal Nature.

The authors recommend the foundation of a powerful global organisation similar to the Intergovernmental Panel on Climate Change (IPCC) to lead an international response.

They argue that the growing threat of antimicrobial resistance is similar to that posed by climate change because it is a natural process exacerbated by human activity and the actions of one country can have global ramifications.

Yet the international response to this threat -- caused by the overuse and misuse of antimicrobial drugs -- has been feeble, the authors say.

They are calling for the creation of an independent body to oversee surveillance efforts and set strict evidence-based targets, to stem the loss of drug potency and speed the development of new therapies.

Such an organisation should work closely with the national governments and international agencies who will be tasked with implementing its recommendations.

In a world without antibiotics, routine surgical procedures would become deadly, scientists say. Treatment for cancer and diabetes, as well as organ transplants, would be impossible in their current form. Industrial agriculture would also suffer, owing to the increased use of antibiotics in animals as growth promoters.

Dr Jeremy Farrar, Director of the Wellcome Trust, a global charitable foundation spending £750 million annually on biomedical research, said: "We have needed to take action against the development of antimicrobial resistance for more than 20 years. Despite repeated warnings, the international response has been feeble. The World Health Organisation has missed opportunities to provide leadership, and very little progress has been made. The result has been the emergence of strains of infections including tuberculosis and malaria, pneumonia and gonorrhoea that resist all known classes of drugs. We need a new independent body that will not only monitor the spread of antimicrobial resistance, but also drive and direct efforts to contain it."

Professor Mark Woolhouse, of the University of Edinburgh's Centre for Immunity, Infection and Evolution, said: "The time has come to stop re-stating the problems of antimicrobial resistance and start taking action. We need independent, international leadership on this issue before the massive health gains that have been made since Alexander Fleming's discovery of penicillin are lost forever."

Story Source:

The above story is based on materials provided by University of Edinburgh. Note: Materials may be edited for content and length.

Journal Reference:

Mark Woolhouse & Jeremy Farrar. Policy: An intergovernmental panel on antimicrobial resistance. Nature, May 2014 DOI: 10.1038/509555a

Stem cell development: Experts offer insight into basic mechanisms of stem cell differentiation

May 22 / 2014

University of Southern Denmark

The world has great expectations that stem cell research one day will revolutionize medicine. But in order to exploit the potential of stem cells, we need to understand how their development is regulated. Now researchers report a new discovery that provides valuable insight into basic mechanisms of stem cell differentiation. The discovery could lead to new ways of making stem cells develop into exactly the type of cells that a physician may need for treating a disease.

Stem cells are cells that are able to develop into different specialized cell types with specific functions in the body. In adult humans these cells play an important role in tissue regeneration. The potential to act as repair cells can be exploited for disease control of e.g. Parkinson's or diabetes, which are diseases caused by the death of specialized cells. By manipulating the stem cells, they can be directed to develop into various specialized cell types. This however, requires knowledge of the processes that regulate their development.

Now Danish researchers from University of Southern Denmark report a new discovery that provides valuable insight into basic mechanisms of stem cell differentiation. The discovery could lead to new ways of making stem cells develop into exactly the type of cells that a physician may need for treating a disease.

"We have discovered that proteins called transcription factors work together in a new and complex way to reprogram the DNA strand when a stem cell develops into a specific cell type. Until now we thought that only a few transcription factors were responsible for this reprogramming, but that is not the case," explain postdoc Rasmus Siersbaek, Professor Susanne Mandrup and ph.d. Atefeh Rabiee from Department of Biochemistry and Molecular Biology at the University of Southern Denmark.

"An incredibly complex and previously unknown interplay between transcription factors takes place at specific locations in the cell's DNA, which we call 'hotspots'. This interplay at 'hotspots' appears to be of great importance for the development of stem cells. In the future it will therefore be very important to explore these 'hotspots' and the interplay between transcription factors in these regions in order to better understand the mechanisms that control the development of stem cells," explains Rasmus Siersbaek.

"When we understand these mechanisms, we have much better tools to make a stem cell develop in the direction we wish," he says.

Siersbaek, Mandrup and their colleagues made the discovery while studying how stem cells develop into fat cells. The Mandrup research group is interested in this differentiation process, because fundamental understanding of this will allow researchers to manipulate fat cell formation.

"We know that there are two types of fat cells; brown and white. The white fat cells store fat, while brown fat cells actually increase combustion of fat. Brown fat cells are found in especially infants, but adults also have varying amounts of these cells.

"If we manage to find ways to make stem cells develop into brown rather than white fat cells, it may be possible to reduce the development of obesity. Our findings open new possibilities to do this by focusing on the specific sites on the DNA where proteins work together," the researchers explain.

Details of the study

The researchers worked with a well-known cell line that can be induced to develop into fat cells in about a week in the laboratory using a specific cocktail of hormones. It has been known for many years that this process is regulated by proteins in the cells called transcription factors that control which genes are turned on and off during development of the fat cell.

So far it has been unclear how all these proteins work together to create a fat cell. In this paper, the researchers report that transcription factors bind together to special places in the cell's genome called 'hotspots' . Here transcription factors 'talk' to each other and cooperate in controlling which genes are switched on and off. 'Hotspots' therefore act as key hubs in the genome where different signals are integrated on a small piece of DNA.

The researchers further showed that there are often several of these 'hotspots' close to each other and that they work together to form large so-called 'super-enhancers' . These 'super-enhancers' seem to be extra important in order to activate the right genes during fat cell development.

This study thus shows an extremely high degree of cooperativity between transcription factors at the level of DNA, which seems to be very important for directing the development of stem cells.

Story Source:

The above story is based on materials provided by University of Southern Denmark. Note: Materials may be edited for content and length.

Journal Reference:

Rasmus Siersbæk, Songjoon Baek, Atefeh Rabiee, Ronni Nielsen, Sofie Traynor, Nicholas Clark, Albin Sandelin, Ole N. Jensen, Myong-Hee Sung, Gordon L. Hager, Susanne Mandrup. Molecular Architecture of Transcription Factor Hotspots in Early Adipogenesis. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.04.043

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Cells: RaDAR guides proteins into the nucleus

May 22 / 2014

Ludwig Institute for Cancer Research

A novel pathway by which proteins are actively and specifically shuttled into the nucleus of a cell has been discovered by scientists. The finding captures a precise molecular barcode that flags proteins for such import and describes the biochemical interaction that drives this critically important process. The discovery could help illuminate the molecular dysfunction that underpins a broad array of ailments, ranging from autoimmune diseases to cancers.

A Ludwig Cancer Research study has identified a novel pathway by which proteins are actively and specifically shuttled into the nucleus of a cell. Published online today in Cell, the finding captures a precise molecular barcode that flags proteins for such import and describes the biochemical interaction that drives this critically important process. The discovery could help illuminate the molecular dysfunction that underpins a broad array of ailments, ranging from autoimmune diseases to cancers.

Although small proteins can diffuse passively through pores built into the nuclear membrane, most nuclear proteins have to be actively driven into the nucleus through specialized pores to ensure that the cell functions normally. Proteins targeted to specific compartments in cells often carry a sequence of amino acids that, like a barcode, tells components of the cell's transport machinery where they should be located in order to perform their biochemical duties.

"Until now, only one nuclear import pathway for active transport has been extensively characterized," says Xin Lu, Ludwig director at the University of Oxford whose laboratory led the study. "It targets proteins that encode what's known as the nuclear localization signal (NLS). Yet about half of the proteins that get into the nucleus do not bear an NLS, and how they get there has long puzzled researchers. Now we have discovered an alternative signal by which proteins devoid of NLS are tagged for nuclear import." The finding will help scientists better understand the roles many hitherto poorly characterized proteins play in cellular life, and identify many others that work within the nucleus on such tasks as gene regulation and expression.

The researchers were led to their discovery while investigating how an important tumor suppressor protein known as ASPP, which Lu's laboratory has been studying for many years, gets into the nucleus. Their experiments revealed that a widely shared element of protein structure found in ASPP, known as the ankyrin repeat (AR), plays a central role in the protein's nuclear localization.

Lu's team shows in the study that the import signal that flags proteins for the new pathway consists of two consecutive ARs that share one feature: each has a hydrophobic amino acid (one with chemical properties that repel water) that is located 13 amino acids into the repeat. This structural signature, they find, is bound by a small protein named RanGDP. Lu and her colleagues have named this new pathway the RaDAR (RanGDP-Ankyrin Repeat) nuclear import pathway. They have so far identified more than 46 proteins encoded by the human genome that carry this barcode for nuclear delivery.

In decoding this new nuclear import signal, Lu and her team also uncover a possible molecular mechanism underlying human familial melanomas, which are often linked to mutations in a protein known as p16. "We show that the p16 mutation most frequently associated with such cancers," Lu explains, "confers the RaDAR barcode to the protein, resulting in its aberrant accumulation in the nucleus." The RaDAR signature is also associated with a number of regulators of cell proliferation and gene regulation, including the NF-kB family of proteins, which shuttle between the cytoplasm and nucleus, and have been implicated in several human cancers, and autoimmune and inflammatory diseases.

Lu's team is now investigating the spectrum of proteins that use the RaDAR pathway and exploring methods by which the ankyrin repeat that bears that barcode might be exploited to develop entirely novel diagnostics and therapies. That includes incorporating the new nuclear import barcode into synthetic molecules named DARPins to target biologics and other kinds of drugs specifically to the nucleus.

Story Source:

The above story is based on materials provided by Ludwig Institute for Cancer Research. Note: Materials may be edited for content and length.

Journal Reference:

Min Lu, Jaroslav Zak, Shuo Chen, Luis Sanchez-Pulido, David T. Severson, Jane Endicott, Chris P. Ponting, Christopher J. Schofield, Xin Lu. A Code for RanGDP Binding in Ankyrin Repeats Defines a Nuclear Import Pathway. Cell, 2014; 157 (5): 1130 DOI: 10.1016/j.cell.2014.05.006

Supportive tumor tissue surrounding cancer cells hinders, rather than helps, pancreatic cancer

Fibrous tissue long suspected of making pancreatic cancer worse actually supports an immune attack that slows tumor progression but cannot overcome it, scientists at The University of Texas MD Anderson Cancer Center report in the journal Cancer Cell.

"This supportive tissue that's abundant in pancreatic cancer tumors is not a traitor as we thought but rather an ally that is fighting to the end. It's a losing battle with cancer cells, but progression is much faster without their constant resistance," said study senior author Raghu Kalluri, Ph.D., M.D., chair of Cancer Biology. "It's like having a car with weak yet functioning brakes vs. having one with no brakes."

The team's findings point to a potential new avenue for guiding treatment, including immunotherapy, and offer an explanation for the failure of a promising combination drug approach in clinical trials.

"Cancer is one form of tissue injury. When our defense system detects damaged cells it sends soldiers to contain and repair the damage," Kalluri said. "When it cannot remove the damaged cells and repair the injured area, our defensive fibrotic response tries to put a boundary around it, to contain it and prevent it from spreading."

Pancreas cancer is resistant to treatment and only about 7 percent of patients survive for five years. An estimated 46,420 new U.S. cases will be diagnosed in 2014 and 39,590 people will die of the disease.

Study results consistent with failed clinical trial

Kalluri and colleagues used genetically engineered mouse models that allowed depletion of tissue-repair cells called myofibroblasts in pancreatic cancer. Myofibroblasts compose a major portion of supportive tissue called stroma and also produce collagen, which serves as a scaffold for wound-healing and tissue regeneration. Up to 90 percent of a pancreas tumor can consist of fibrotic support tissue.

When the scientists depleted myofibroblast production in mice with either early or later-stage pancreatic ductal adenocarcinoma their tumors became much more invasive, aggressive and lethal.

"We did these experiments thinking that we would show the importance of myofibroblasts and fibrosis in pancreas cancer progression, but the results went completely against that hypothesis," Kalluri said.

Since myofibroblasts and collagen are thought to block chemotherapy, the team treated their myofibroblast-depleted mice with gemcitabine, the standard treatment for pancreas cancer. The drug did not have any effect on the disease course or improve survival.

These results track those of a major clinical trial that combined a myofibroblast-depleting drug called a hedgehog inhibitor with gemcitabine to treat pancreatic cancer patients. The trial was stopped in 2012 when an interim analysis showed the patients taking the combination had faster disease progression than the control group that took only gemcitabine, a surprising result.

"This paradigm-shifting study identifies the reason why the hedgehog-inhibitor trials failed," said co-author Anirban Maitra, M.D., professor of Pathology and scientific director of the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research.

All solid tumors include some degree of fibrosis, Maitra said, but not as much as pancreas cancer.

The team's analysis of pancreatic tumors from 53 patients showed low levels of tumor myofibroblasts are associated with decreased survival.

Study findings are consistent with pathologic evidence that tumors with more fibrotic tissue more closely resemble normal pancreas tissue, indicating a better prognosis for patients, even though lab experiments indicated those tumors should be more aggressive, Maitra said.

"These findings also are likely to account for rather modest results in a phase I clinical trial of immunotherapy alone for pancreas cancer," Maitra said. "But it's not just a negative study, because it suggests what might work for these patients."

And what might work hinges on immune checkpoint blockade.

The immune system connection

To understand the cause of the swift progression, the team conducted gene expression profiling and RNA sequence analysis comparing control tumors to myofibroblast-depleted tumors.

Genes associated with tumor immunity were suppressed and fewer T cells and B cells infiltrated the myofibroblast-depleted tumors. The proportion of regulatory T cells, which suppress immune response, increased. They found greater expression of the immune checkpoint CTLA-4, which shuts down immune response.

The researchers then set up a new experiment using ipilimumab, a drug developed by co-author Jim Allison, Ph.D., chair of Immunology, that blocks CTLA-4, freeing T cells to attack tumors. Mice with depleted myofibroblasts who were treated with ipilimumab to stifle CTLA-4 had an average survival increase of 60% compared to untreated control mice and those with either depleted myofibroblasts or treated with ipilimumab alone.

These findings suggest that ipilimumab might work for patients with low levels of fibrosis in their tumors, Kalluri noted. Combining ipilimumab with a hedgehog inhibitor is likely to work better for those with high-fibrosis. The Kalluri laboratory is exploring these issues.

Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.

Journal Reference:

Berna C. Özdemir, Tsvetelina Pentcheva-Hoang, Julienne L. Carstens, Xiaofeng Zheng, Chia-Chin Wu, Tyler R. Simpson, Hanane Laklai, Hikaru Sugimoto, Christoph Kahlert, Sergey V. Novitskiy, Ana De Jesus-Acosta, Padmanee Sharma, Pedram Heidari, Umar Mahmood, Lynda Chin, Harold L. Moses, Valerie M. Weaver, Anirban Maitra, James P. Allison, Valerie S. LeBleu, Raghu Kalluri. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell, 2014; DOI: 10.1016/j.ccr.2014.04.005

Genes discovered linking circadian clock with eating schedule

May 22 / 2014

Salk Institute for Biological Studies

For most people, the urge to eat a meal or snack comes at a few, predictable times during the waking part of the day. But for those with a rare syndrome, hunger comes at unwanted hours, interrupts sleep and causes overeating. "We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle," says the senior study author. "It opens up a whole lot of future questions about how these cycles are regulated."

Caption: Mice with a mutation in the PER2 gene (top right) have an altered sleep cycle, while those with a mutation in the PER1 gene (bottom right) have an abnormal eating schedule.

Now, Salk scientists have discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms, and, when mutated, may play a role in so-called night eating syndrome. In mice with mutations in one of the genes, eating patterns are shifted, leading to unusual mealtimes and weight gain. The results were published in this month's Cell Reports.

"We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle, especially with a simple mutation," says senior study author Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory. "It opens up a whole lot of future questions about how these cycles are regulated."

More than a decade ago, researchers discovered that individuals with an inherited sleep disorder often carry a particular mutation in a protein called PER2. The mutation is in an area of the protein that can be phosphorylated -- the ability to bond with a phosphate chemical that changes the protein's function. Humans have three PER, or period, genes, all thought to play a role in the daily circadian clock and all containing the same phosphorylation spot.

The Salk scientists joined forces with a Chinese team led by Ying Xu of Nanjing University to test whether mutations in the equivalent area of PER1 would have the same effect as those in PER2 that caused the sleep disorder. So they bred mice to lack the mouse period genes, and added in a human PER1 or PER2 with a mutation in the phosphorylation site. As expected, mice with a mutated PER2 had sleep defects, dozing off earlier than usual. The same wasn't true for PER1 mutations though.

"In the mice without PER1, there was no obvious defect in their sleep-wake cycles," says Panda. "Instead, when we looked at their metabolism, we suddenly saw drastic changes."

Mice with the PER1 phosphorylation defects ate earlier than other mice -- causing them to wake up and snack before their sleep cycle was over -- and ate more food throughout their normal waking period. When the researchers looked at the molecular details of the PER1 protein, they found that the mutated PER1 led to lower protein levels during the sleeping period, higher levels during the waking period, and a faster degradation of protein whenever it was produced by cells.

Panda and his colleagues hypothesize that normally, PER1 and PER2 are kept synchronized since they have identical phosphorylation sites -- they are turned on and off at the same times, keeping sleep and eating cycles aligned. But a mutation in one of the genes could break this link, and cause off-cycle eating or sleeping.

"For a long time, people discounted night eating syndrome as not real," says Panda. "These results in mice suggest that it could actually be a genetic basis for the syndrome." The researchers haven't yet tested, however, whether any humans with night eating syndrome have mutations in PER1.

When Panda and Xu's team restricted access to food, providing it only at the mice's normal meal times, they found that even with a genetic mutation in PER1, mice could maintain a normal weight. Over a 10-week follow-up, these mice -- with a PER1 mutation but timed access to food -- showed no differences to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.

Next, they hope to study exactly how PER1 controls appetite and eating behavior -- whether its molecular actions work through the liver, fat cells, brain or other organs.

Story Source:

The above story is based on materials provided by Salk Institute for Biological Studies. Note: Materials may be edited for content and length.

Journal Reference:

Zhiwei Liu, Moli Huang et al. PER1 Phosphorylation Specifies Feeding Rhythm in Mice. Cell Reports, May 2014 DOI: 10.1016/j.celrep.2014.04.032